The general goals of this COBRE project are to increase understanding of the self/non-self recognition mechanisms in RNAi, a fundamental aspect of genetic immunity; to build predictive models of RNAi for targeting specific genes and/or general gene families; to use advanced machine learning techniques to develop theoretical models and understanding of the RNAi matching function; to develop new, advanced machine learning techniques for bioinformatic domains and migrate them into the theoretical immunology community; to develop novel algorithms motivated by models of the RNA silencing mechanism; and to initiate a significant line of bioinformatic research in the investigator?s career which will help align the research directions with NIH goals and prepare the investigator to secure independent NIH funding. I will accomplish these goals through the following specific aims: Specific Aim 1: Machine Learning Software Acquisition and Development; Specific Aim 2: Abstract Models of RNA Silencing and Computer Virus Detection; Specific Aim 3: Extension of RNAi Models; Specific Aim 4: Empirical Validation and Model Refinement.